The present invention relates to a new process for the preparation of 5-fluorocytosine, which can also be called 2-hydroxy-4-amino-5-fluoropyrimidine.
5-Fluorocytosine is known as a pharmaceutical and as an intermediate for the preparation of pharmacologically active substances (see, for example, R. Filler and S. M. Naqvi in "Biomedicinal Aspects of Fluorine Chemistry", Eds. R. Filler and Y. Kobayashi, Elsevier, Amsterdam-New York-Oxford, 1982). It was hitherto prepared by direct fluorination of cytosine (see U.S. Pat. No. 3,846,429 and Canadian Patent Specification No. 985,681), which required industrially expensive handling of elemental fluorine, or by expensive cyclization reactions of .alpha.-fluoro-.beta.-keto-ester enolates with salts of isothioureas (see J. Am. Chem. Soc. 79, 4559 (1957)).
Another synthesis starts from 5-fluorouracil, a compound which can also be prepared only in an expensive manner by direct fluorination of the uracil with elemental fluorine (see U.S. Pat. No. 3,846,429 and Canadian Patent Specification No. 985,681), or by expensive cyclization reactions (see J. Am. Chem. Soc. 79, 4559 (1957)). The 5-fluorouracil must then also be further converted into 2,4-dichloro-5-fluoropyrimidine with phosphorus oxychloride. The amino group is subsequently introduced into the 4-position and the hydroxyl group is then introduced into the 2-position and, finally, 2-hydroxy-4-amino-5-fluoropyrimidine (=5-fluorocytosine) is thus obtained (see British Patent Specification 877,318). This route comprises many individual stages and is therefore very difficult, and uses 5-fluorouracil, which is accessible only with difficulty, as the starting substance.
It is also known that 2-hydroxy-4-chloro-5-fluoropyrimidine--this compound is encountered as an intermediate in the process according to the invention--can be synthesized by a process in which 5-fluorouracil is again used as the starting substance and is sulphurized in the 4-position with P.sub.2 S.sub.5, and the compound then obtained, that is to say 5-fluoropyrimidine-2-one-4-thione, is subsequently converted into 2-hydroxy-4-chloro-5-fluoropyrimidine with thionyl chloride (see Acta Chem. Scand. 23, 294 (1969)). This process has the disadvantage that more expensive reagents than in the process according to the invention are employed and more expensive working up and disposal measures must be taken. In addition, the yield in the last stage is only 45% of theory.